On Thursday, the US Food and Drug Administration advised vaccine makers to reformulate COVID-19 booster shots for this fall. The boosters would target both the original strain of the pandemic coronavirus plus two new omicron subvariants—BA.4 and BA.5—which became the dominant versions of the virus circulating in the United States this week.

The FDA’s announcement comes two days after its independent expert advisors voted overwhelmingly in favor of updating boosters to include an omicron component. The vote—19 in favor, two against—was simply in favor of including an omicron component generally. But, in their afternoon-long discussion, experts offered opinions that led to the FDA’s more specific guidance.

Specifically, much of the committee expressed support for combination shots—aka bivalent boosters—that would target both the original virus and a version of omicron. There was also broad support for targeting the omicron subvariants BA.4 and BA.5 specifically, rather than earlier subvariants, such as the first, BA.1, which is no longer in circulation.

BA.4 and BA.5 subvariants share an identically mutated spike protein, which is critical for infection and the target of COVID-19 vaccines. This similarity is why the two are often lumped together, despite having different mutations elsewhere in their genomes. This week, BA.4 and BA.5 collectively achieved dominance in the US, accounting for an estimated 52 percent of infections, according to the latest Centers for Disease Control and Prevention data. BA.5 is ahead, accounting for 36.6 percent, with BA.4 accounting for 15.7 percent.

The pair are significantly different from previous versions of omicron; They have a transmission advantage compared with other subvariants and are even better at evading vaccine- and infection-based immunity. For these reasons, the FDA’s experts felt the next generation of boosters should target BA.4/5 rather than bygone omicron subvariants.

FDA’s move

But this is somewhat of a gamble—and a time crunch. So far, leading vaccine makers Moderna and Pfizer-BioNTech have focused on updated vaccines that target the original omicron variant, BA.1. The vast majority of data available on next-generation boosters involves BA.1, either in bivalent formulas or alone. There is no clinical data on the efficacy of BA.4/5 vaccines yet.

But, if the FDA waits longer to recommend a reformulation, the doses won’t be ready for fall and winter. And this is critical to the FDA, which sees fall as primetime for a new infection surge. At that time, protection from current vaccine doses will be waning and cold weather will drive people indoors, where the risk of transmission is highest. Even with the FDA recommendation coming today, June 30, vaccine makers will be under pressure to get doses out by October or early November.

That means manufacturing will start while clinical data on BA.4/5 vaccines is still being collected and reviewed. In a statement Thursday, FDA’s top vaccine regulator Peter Marks assured Americans that “any COVID-19 vaccine authorized or approved by the FDA will meet our standards for safety and effectiveness.”

His statement continued:

Vaccine manufacturers have already reported data from clinical trials with modified vaccines containing an omicron BA.1 component and we have advised them that they should submit these data to the FDA for our evaluation prior to any potential authorization of a modified vaccine containing an omicron BA.4/5 component. Manufacturers will also be asked to begin clinical trials with modified vaccines containing an omicron BA.4/5 component, as these data will be of use as the pandemic further evolves.

Readiness and wariness

In a tweet Thursday, Pfizer CEO Albert Bourla said the company and its partner, BioNTech, are following the FDA’s guidance to “develop a bivalent Omicron BA.4/BA.5 subvariant vaccine booster to help protect people, subject to regulatory authorization, as we enter the next chapter of the #COVID19 pandemic.” Bourla added that the mRNA-based vaccine platform allows for relatively fast adjustments and that the company is “ready to immediately implement this process.”

Still, some experts are wary of the FDA’s approach, including pediatrician Paul Offit, the director of the Vaccine Education Center at the Children’s Hospital of Philadelphia, and a member of the FDA’s expert advisor panel—one of the two members who voted against updating the booster doses with an omicron component.

In an opinion piece published in Stat News on Wednesday, Offit and John Moore, a microbiology and immunology professor at Weill Cornell Medicine, argued that the FDA should wait for more data on omicron-focused boosters before making the recommendation it made today. They argue that a BA.4/5 booster may not end up being significantly better than current vaccines against BA.4/5 and may not offer strong protection against whatever comes next.

“A multibillion-dollar decision to launch a vaccine based wholly or in part on the BA.1, BA.4, or BA.5 sequence that would affect more than 100 million people need not be unduly rushed,” Offit and Moore wrote Wednesday, before the FDA’s recommendation. The FDA’s decision, they say,  was made “without fully weighing what the exact composition of the new vaccine should be, and assessing whether it confers significant advantages over the current vaccine.”

https://arstechnica.com/?p=1863897